Reviewed, UniProtKB/Swiss-Prot Q96RU7 (TRIB3_HUMAN)

Names and origin

Protein names

Recommended name:
    Tribbles homolog 3
      Short name=TRB-3
Alternative name(s):
    Neuronal cell death-inducible putative kinase
    p65-interacting inhibitor of NF-kappa-B
    SINK

Gene names

Name:	TRIB3
Synonyms:	C20orf97, NIPK, SKIP3, TRB3

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	358 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Disrupts insulin signaling by binding directly to Akt kinases and blocking their activation. May bind directly to and mask the 'Thr-308' phosphorylation site in AKT1. Binds to ATF4 and inhibits its transcriptional activation activity. Interacts with the NF-kappa-B transactivator p65 RELA and inhibits its phosphorylation and thus its transcriptional activation activity. Interacts with MAPK kinases and regulates activation of MAP kinases. May play a role in programmed neuronal cell death but does not appear to affect non-neuronal cells. Does not display kinase activity. Ref.2 Ref.3 Ref.4
Subunit structure	Interacts with AKT1, AKT2, ATF4, MAP2K1 and MAP2K7. Ref.2 Ref.3 Ref.1
Subcellular location	Nucleus Probable.
Tissue specificity	Highest expression in liver, pancreas, peripheral blood leukocytes and bone marrow. Also highly expressed in a number of primary lung, colon and breast tumors. Expressed in spleen, thymus, and prostate and is undetectable in other examined tissues, including testis, ovary, small intestine, colon, leukocyte, heart, brain, placenta, lung, skeletal muscle, and kidney. Ref.2 Ref.3 Ref.1
Induction	By hypoxia, TNF and by nutrient starvation. Expression is PI 3-kinase and/or NF-kappa-B-dependent. Ref.2 Ref.1 Ref.11
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Tribbles subfamily. Contains 1 protein kinase domain.
Caution	The role of this protein in Akt activation has been demonstrated by Du et al (PubMed:12791994) for the mouse ortholog but Iynedjian (PubMed:15469416) has not been able to reproduce the result in rat hepatocytes.

Ontologies

Keywords
Biological process	Apoptosis Stress response Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Molecular function	Protein kinase inhibitor
Gene Ontology (GO)
Biological process	apoptosis Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of protein kinase activity Inferred from sequence or structural similarity. Source: UniProtKB protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro regulation of MAP kinase activity Ref.3 Inferred from direct assay. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW response to stress Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	ATP binding Inferred from electronic annotation. Source: InterPro protein kinase activity Inferred from electronic annotation. Source: InterPro protein kinase binding Ref.3 Inferred from physical interaction. Source: UniProtKB protein kinase inhibitor activity Inferred from electronic annotation. Source: UniProtKB-KW transcription corepressor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATF4	P18848	1	EBI-492476,EBI-492498
MAP2K1	Q02750	1	EBI-492476,EBI-492564
MAP2K7	O14733	1	EBI-492476,EBI-492605

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 358	358	Tribbles homolog 3		PRO_0000131866
Regions
	Domain	68 – 316	249	Protein kinase
Natural variations
	Natural variant	60	1	T → I in a glioblastoma multiforme sample; somatic mutation. Ref.12		VAR_042372
	Natural variant	84	1	Q → R: dbSNP rs2295490. Ref.12 Ref.10		VAR_023965
	Natural variant	153	1	R → H: dbSNP rs35051116. Ref.12		VAR_042373
	Natural variant	274	1	R → H Ref.12		VAR_042374
	Natural variant	347	1	E → K Ref.12		VAR_042375
Experimental info
	Sequence conflict	24	1	N → D in CAG33647. Ref.7
	Sequence conflict	105	1	L → P Ref.6
	Sequence conflict	105	1	L → P Ref.8
	Sequence conflict	114	1	L → V in AAK58175. Ref.3
	Sequence conflict	194 – 195	2	ER → DREK in AAK58175. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q96RU7-1 [UniParc]. Last modified February 1, 2003. Version 2. Checksum: CE15FD89A81E8D63	FASTA	358	39,578
	10 20 30 40 50 60 MRATPLAAPA GSLSRKKRLE LDDNLDTERP VQKRARSGPQ PRLPPCLLPL SPPTAPDRAT 70 80 90 100 110 120 AVATASRLGP YVLLEPEEGG RAYQALHCPT GTEYTCKVYP VQEALAVLEP YARLPPHKHV 130 140 150 160 170 180 ARPTEVLAGT QLLYAFFTRT HGDMHSLVRS RHRIPEPEAA VLFRQMATAL AHCHQHGLVL 190 200 210 220 230 240 RDLKLCRFVF ADRERKKLVL ENLEDSCVLT GPDDSLWDKH ACPAYVGPEI LSSRASYSGK 250 260 270 280 290 300 AADVWSLGVA LFTMLAGHYP FQDSEPVLLF GKIRRGAYAL PAGLSAPARC LVRCLLRREP 310 320 330 340 350 AERLTATGIL LHPWLRQDPM PLAPTRSHLW EAAQVVPDGL GLDEAREEEG DREVVLYG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia." Bowers A.J., Scully S., Boylan J.F. Oncogene 22:2823-2835(2003) [PubMed: 12743605] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INDUCTION, INTERACTION WITH ATF4.
[2]	"SINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription." Wu M., Xu L.G., Zhai Z., Shu H.B. J. Biol. Chem. 278:27072-27079(2003) [PubMed: 12736262] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, INDUCTION, INTERACTION WITH RELA.
[3]	"Human tribbles, a protein family controlling mitogen-activated protein kinase cascades." Kiss-Toth E., Bagstaff S.M., Sung H.Y., Jozsa V., Dempsey C., Caunt J.C., Oxley K.M., Wyllie D.H., Polgar T., Harte M., O'Neill L.A.J., Qwarnstrom E.E., Dower S.K. J. Biol. Chem. 279:42703-42708(2004) [PubMed: 15299019] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH MAP2K1 AND MAP2K7.
[4]	"Characterization of human NIPK (TRB3, SKIP3) gene activation in stressful conditions." Ord D., Ord T. Biochem. Biophys. Res. Commun. 330:210-218(2005) [PubMed: 15781252] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[5]	Shan Y.X., Yu L. Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[8]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver.
[9]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-84. Tissue: Cervix and Muscle.
[11]	"TRB3 is a PI 3-kinase dependent indicator for nutrient starvation." Schwarzer R., Dames S., Tondera D., Klippel A., Kaufmann J. Cell. Signal. 18:899-909(2006) [PubMed: 16129579] [Abstract] Cited for: INDUCTION.
[12]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ILE-60; ARG-84; HIS-153; HIS-274 AND LYS-347.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF250311 mRNA. Translation: AAK58175.1. AJ697936 mRNA. Translation: CAG27047.1. AY247738 mRNA. Translation: AAP04407.1. AK026945 mRNA. Translation: BAB15597.1. CR457366 mRNA. Translation: CAG33647.1. AK222837 mRNA. Translation: BAD96557.1. AL034548 Genomic DNA. Translation: CAB81634.1. BC019363 mRNA. Translation: AAH19363.1. BC027484 mRNA. Translation: AAH27484.1.
IPI	IPI00290307.
RefSeq	NP_066981.2.
UniGene	Hs.516826
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	Q96RU7. 12 interactions.
Proteomic databases
PRIDE	Q96RU7.
Genome annotation databases
Ensembl	ENSG00000101255. Homo sapiens. [Contig view]
GeneID	57761.
KEGG	hsa:57761.
Organism-specific databases
GeneCards	GC20P000309.
HGNC	HGNC:16228. TRIB3.
HPA	HPA015272.
MIM	607898. gene.
PharmGKB	PA25804.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q96RU7.
OMA	Q96RU7. LWDKHAC.
Enzyme and pathway databases
Reactome	REACT_11061. Signalling by NGF. REACT_498. Signaling by Insulin receptor.
Gene expression databases
ArrayExpress	Q96RU7.
Bgee	Q96RU7.
CleanEx	HS_TRIB3.
GermOnline	ENSG00000101255. Homo sapiens.
Family and domain databases
InterPro	IPR000719. Prot_kinase_core. IPR017442. Se/Thr_pkinase-rel. [Graphical view]
Pfam	PF00069. Pkinase. 2 hits. [Graphical view]
ProDom	PD000001. Prot_kinase. 1 hit. [Graphical view] [Entries sharing at least one domain]
PROSITE	PS50011. PROTEIN_KINASE_DOM. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	64708.
SOURCE	Search...

Entry information

Entry name

TRIB3_HUMAN

Accession

Primary (citable) accession number: Q96RU7
Secondary accession number(s): Q53GU4 , Q53ZW7, Q6I9Y9, Q8TAI6, Q9H5M8, Q9NUD2

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 2003
Last sequence update:	February 1, 2003
Last modified:	June 16, 2009
This is version 73 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)